Causal relationship between bone mineral density and intervertebral disc degeneration: a univariate and multivariable mendelian randomization study.

BACKGROUND: Although previous studies have suggested a possible association between bone mineral density (BMD) and intervertebral disc degeneration (IDD), the causal relationship between them remains unclear. Evidence from accumulating studies indicates that they might mutually influence one another. However, observational studies may be affected by potential confounders. Meanwhile, Mendelian randomization (MR) study can overcome these confounders to assess causality. OBJECTIVES: This Mendelian randomization (MR) study aimed to explore the causal effect of bone mineral density (BMD) on intervertebral disc degeneration (IDD). METHODS: Summary data from genome-wide association studies of bone mineral density (BMD) and IDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran's Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. Multivariate MR (MVMR) analyses used multivariable inverse variance-weighted methods to individually and jointly adjust for four potential confounders, body mass index (BMI), Type2 diabetes, hyperthyroidism and smoking. A reverse MR analysis was conducted to assess potential reverse causation. RESULTS: In the univariate MR analysis, femoral neck bone mineral density (FNBMD), heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) had a direct causal effect on intervertebral disc degeneration (IDD) [FNBMD-related analysis: OR(95%CI) = 1.17 (1.04 to 1.31), p = 0.008, eBMD-related analysis: OR(95%CI) = 1.06 (1.01 to 1.12), p = 0.028, LSBMD-related analysis: OR(95%CI) = 1.20 (1.10 to 1.31), p = 3.38E-7,TB BMD-related analysis: OR(95%CI) = 1.20 (1.12 to 1.29), p = 1.0E-8]. In the MVMR analysis, it was revealed that, even after controlling for confounding factors, heel bone mineral density (eBMD), lumbar spine bone mineral density (LSBMD), and total body bone mineral density (TB BMD) still maintained an independent and significant causal association with IDD(Adjusting for heel bone mineral density: beta = 0.073, OR95% CI = 1.08(1.02 to 1.14), P = 0.013; Adjusting for lumbar spine bone mineral density: beta = 0.11, OR(95%CI) = 1.12(1.02 to 1.23), P = 0.03; Adjusting for total body bone mineral density: beta = 0.139, OR95% CI = 1.15(1.06 to 1.24), P = 5.53E - 5). In the reverse analysis, no evidence was found to suggest that IDD has an impact on BMD. CONCLUSIONS: The findings from our univariate and multivariable Mendelian randomization analysis establish a substantial positive causal association between BMD and IDD, indicating that higher bone mineral density may be a significant risk factor for intervertebral disc degeneration. Notably, no causal effect of IDD on these four measures of bone mineral density was observed. Further research is required to elucidate the underlying mechanisms governing this causal relationship.

A Feasibility Study on Using Hanging Arm Test to Assess Elbow Stability During Surgical Treatment for Varus Posteromedial Rotatory Instability.

Objectives: The aim of this study to investigate the safety and effectiveness of performing the hanging arm test during surgical treatment for elbow varus posteromedial rotatory instability (VPMRI) to assess elbow stability and determine whether to repair the lateral ulnar collateral ligament (LUCL). Methods: In a retrospective study from August 2014 to March 2019, 27 patients with VPMRI who had a negative result in the hanging arm test after fixation of coronoid fracture were selected. Intraoperative bleeding, operative time, elbow range of motion (ROM), and complications were recorded. Elbow function was evaluated with the Mayo elbow performance score (MEPS) and the disabilities of the arm, shoulder, and hand (DASH) score. Results: The operation time was 85.9 ± 11.06 min (range 65-110). The intraoperative blood loss was 70.7 ± 9.31 ml (range 60-100). At the last follow-up, the elbow joint averaged 73.8° ± 2.931° in pronation, 78.9° ± 2.941° in supination, 7.2° ± 3.207° in extension, and 123.3° ± 6.651° in flexion. The MEPS score was 90.7 ± 4.36 (range 74-95), and the DASH score was 9.8 ± 2.58 (range 6.67-13.3). One patient presented with symptoms of ulnar nerve entrapment 2 months after operation and was treated with ulnar nerve release. The symptom of numbness went away completely 1 week after operation. No complications such as wound infection, arthritis, or chronic instability of the elbow were found in the other patients. Conclusion: Our findings suggest that not all VPMRI patients need the LUCL to be repaired, and the hanging arm test is a safe and reliable method to assess whether to repair the LUCL in the treatment of elbow VPMRI. Level of evidence: Level IV; Retrospective studies.

Fault anomaly detection method of aero-engine rolling bearing based on distillation learning.

In this study, we address the issue of limited generalization capabilities in intelligent diagnosis models caused by the lack of high-quality fault data samples for aero-engine rolling bearings. We provide a fault anomaly detection technique based on distillation learning to address this issue. Two Vision Transformer (ViT) models are specifically used in the distillation learning process, one of which serves as the teacher network and the other as the student network. By using a small-scale student network model, the computational efficiency of the model is increased without sacrificing model accuracy. For feature-centered representation, new loss and anomaly score functions are created, and an enhanced Transformer encoder with the residual block is proposed. Then, a rolling bearing dynamics simulation method is used to obtain rich fault sample data, and the pre-training of the teacher network is completed. For anomaly detection, the training of the student network is completed based on the proposed loss function and the pre-trained teacher network, using only the vibration acceleration samples obtained from the normal state. Finally, the trained completed network and the designed anomaly score function are used to achieve the anomaly detection of rolling bearing faults. The experimental validation was carried out on two sets of test data and one set of real vibration data of a whole aero-engine, and the detection accuracy reached 100 %. The results show that the proposed method has a high capability of rolling bearing fault anomaly detection.

A New Dual-Input Deep Anomaly Detection Method for Early Faults Warning of Rolling Bearings.

To address the problem of low fault diagnosis accuracy caused by insufficient fault samples of rolling bearings, a dual-input deep anomaly detection method with zero fault samples is proposed for early fault warning of rolling bearings. First, the main framework of dual-input feature extraction based on a convolutional neural network (CNN) is established, and the two outputs of the main frame are subjected to the autoencoder structure. Then, the secondary feature extraction is performed. At the same time, the experience pool structure is introduced to improve the feature learning ability of the network. A new objective loss function is also proposed to learn the network parameters. Then, the vibration acceleration signal is preprocessed by wavelet to obtain multiple signals in different frequency bands, and the two signals in the high-frequency band are two-dimensionally encoded and used as the network input. Finally, the unsupervised learning of the model is completed on five sets of actual full-life rolling bearing fault data sets relying only on some samples in a normal state. The verification results show that the proposed method can realize earlier than the RMS, Kurtosis, and other features. The early fault warning and the accuracy rate of more than 98% show that the method is highly capable of early fault warning and anomaly detection.

Dynamic changes of enhancer and super enhancer landscape in degenerated nucleus pulposus cells.

Inflammatory cascade and extracellular matrix remodeling have been identified as pivotal pathological factors in the progression of intervertebral disc degeneration (IDD), but the mechanisms underlying the aberrant activation of transcription during nucleus pulposus (NP) cell degeneration remain elusive. Super-enhancers (SEs) are large clusters of adjacent lone enhancers, which control expression modes of cellular fate and pathogenic genes. Here, we showed that SEs underwent tremendous remodeling during NP cell degeneration and that SE-related transcripts were most abundant in inflammatory cascade and extracellular matrix remodeling processes. Inhibition of cyclin-dependent kinase 7, a transcriptional kinase-mediated transcriptional initiation in trans-acting SE complex, constricted the transcription of inflammatory cascades, and extracellular matrix remodeling-related genes such as IL1ß and MMP3 in NP cells, meanwhile, also restrained the transcription of Mmp16, Tnfrsf21, and Il11ra1 to retard IDD in rats. In summary, our findings clarify SEs control the transcription of genes associated with inflammatory cascade and extracellular matrix remodeling during NP cell degeneration and identify inhibition of the cyclin-dependent kinase 7, required for SE-mediated transcriptional activation, as a therapeutic option for IDD.

Development of a Risk Score Model for Osteosarcoma Based on DNA Methylation-Driven Differentially Expressed Genes.

Osteosarcoma (OS) is the commonest malignant bone tumor in adolescent patients, and patients face amputation, tumor metastasis, chemotherapy resistance, and even death. We investigated the potential connection between abnormal methylation differentially expressed genes and the survival rate of osteosarcoma patients. GSE36002 and GSE12865 datasets of GEO database were utilized for abnormal methylation differentially expressed genes, followed by function and pathway enrichment analyses, the protein-protein interaction network in the STRING database, and cluster analysis in the MCODE app of Cytoscape. The RNA-seq and clinical data from the TARGET-OS project of TCGA were used for univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses to predict the risk genes of osteosarcoma. 1191 hypermethylation-downregulated genes might function through plasma membrane, negative regulation of transcription from the RNA polymerase II promoter, and pathways, including transcriptional misregulation in cancer. 127 hypomethylation-upregulated genes were enriched in proteolysis, negative regulation of the canonical Wnt signaling pathway, and metabolic signaling pathways. The univariate Cox analysis revealed 638 genes (P < 0.01), including 50 hypermethylation-downregulated genes and 4 hypomethylation-upregulated genes, subsequently based on LASSO Cox regression analysis for 54 aberrant methylation-driven genes, and three genes (COL13A1, MXI1, and TBRG1) were selected to construct the risk score model. The three genes (COL13A1, MXI1, and TBRG1) regulated by DNA methylation were identified to relate with the outcomes of OS patients, which might provide a new insight to the pathological mechanism of osteosarcoma.

Deep Scale-Variant Network for Femur Trochanteric Fracture Classification with HP Loss.

Achieving automatic classification of femur trochanteric fracture from the edge computing device is of great importance and value for remote diagnosis and treatment. Nevertheless, designing a highly accurate classification model on 31A1/31A2/31A3 fractures from the X-ray is still limited due to the failure of capturing the scale-variant and contextual information. As a result, this paper proposes a deep scale-variant (DSV) network with a hybrid and progressive (HP) loss function to aggregate more influential representations of the fracture regions. More specifically, the DSV network is based on the ResNet and integrated with the designed scale-variant (SV) layer and HP loss, where the SV layer aims to enhance the representation ability to extract the scale-variant features, and HP loss is intended to force the network to condense more contextual clues. Furthermore, to evaluate the effect of the proposed DSV network, we carry out a series of experiments on the real X-ray images for comparison and evaluation, and the experimental results demonstrate that the proposed DSV network could outperform other classification methods on this classification task.

N6-methyladenosine methyltransferase WTAP-stabilized FOXD2-AS1 promotes the osteosarcoma progression through m6A/FOXM1 axis.

Long noncoding RNAs (lncRNAs) play critical roles in tumor progression regulation, including osteosarcoma. Evidence indicates that N6-methyladenosine (m6A) modification modulates mRNA stability to regulate osteosarcoma tumorigenesis. Here, present research aims to detect the roles of m6A-modified lncRNA FOXD2-AS1 in the osteosarcoma pathophysiological process. Clinical data unveiled that osteosarcoma patients with higher FOXD2-AS1 expression had a poorer overall survival rate compared to those with lower FOXD2-AS1 expression. Functional research illuminated that FOXD2-AS1 accelerated the migration, proliferation and tumor growth in vitro and in vivo. Mechanistically, a remarkable m6A-modified site was found on the 3'-UTR of FOXD2-AS1, and m6A methyltransferase WTAP (Wilms' tumor 1 associated protein) promoted the methylation modification, thus enhancing the stability of FOXD2-AS1 transcripts. Furthermore, FOXD2-AS1 interacted with downstream target FOXM1 mRNA through m6A sites, forming a FOXD2-AS1/m6A/FOXM1 complex to heighten FOXM1 mRNA stability. In conclusion, these findings propose a novel regulatory mechanism in which m6A-modified FOXD2-AS1 accelerates the osteosarcoma progression through m6A manner, which may provide new concepts for osteosarcoma tumorigenesis.

HIF-1α induced long noncoding RNA FOXD2-AS1 promotes the osteosarcoma through repressing p21.

Emerging literature indicates the essential roles of long noncoding RNA (lncRNA) in the osteosarcoma (OS). However, the regulatory function and mechanism of FOXD2-AS1 in the OS is still elusive. In present research, the level of FOXD2-AS1 was significantly up-regulated in the OS tissue and cell lines compared to corresponding controls. The aberrant high-expression of FOXD2-AS1 indicated the poor clinical prognosis of OS patients. Transcription factor HIF-1α could bind with the promoter region of FOXD2-AS1 to activate the transcription in OS cells. Functionally, the knockdown of FOXD2-AS1 could repress the malignant biological properties of OS cells in vitro and vivo, including proliferation, invasion, apoptosis and tumor growth. Mechanistically, FOXD2-AS1 inhibited the expression of p21 via interacting with EZH2 to silence p21 gene expression. Overall, we conclude that FOXD2-AS1, induced by transcription factor HIF-1α, acts as an oncogene in the OS tumorigenesis and FOXD2-AS1 interacts with EZH2 to silence p21 protein. This finding could provide a novel insight and potential therapeutic target for the OS.

Effect and mechanism of lncRNA HIT on cisplatin resistance in osteosarcoma tissues and U2OS cells / 中国肿瘤生物治疗杂志

@# Objective: To investigate the relationship between long non-coding RNA (lncRNA) HIT and cisplatin (DDP) resistance in osteosarcoma cells and the mechanism related to epithelial-mesenchymal transition (EMT). Methods: 42 pairs of osteosarcoma tissues and corresponding para-cancerous tissues (more than 5 cm away from the edge of cancer tissues) were collected at the Department of Orthopedics, Tianjin Hospital during June 2017 to June 2018. Quantitative Real-time PCR (qRT-PCR) was used to detect the mRNAexpression of HIT and EMT related markers (Snail and E-cadherin) in the collected tissues. The DDP-resistant osteosarcoma U2OS cell line was constructed and human adrenal 293T cell line was used as control. Two sets of siRNA vectors targeting HIT loaded on lentivirus were transfected into cells with DDP-resistance as the interference group A and group B. Meanwhile, the U2OS cell line was transfected with HIT full-length vector and blank vector respectively, as over-expression group and blank group. The DDP 50% inhibitory concentration (IC50) was detected by MTT assay. qRT-PCR was used to detect the mRNA expressions of HIT, Snail and E-cadherin. Western blotting was used to detect the protein expressions of Snail and E-cadherin. RNA binding protein immunoprecipitation (RNAIP) assay was used to clarify the combination of HIT and Snail protein in the U2OS and 293T cells. Results: The mRNAexpressions of HIT and Snail in osteosarcoma tissues were significantly higher than those in para-cancerous tissues, while the mRNA expression of Ecadherin was significantly lower than that in the paracancerous tissues. The mRNA expression of HIT and E-cadherin in osteosarcoma tissues was negatively correlated (all P<0.01). The DDP IC50 in the DDP-resistance group was significantly higher than that in the control group, interference group A and B, and the DDP IC50 in over-expression group was significantly higher than that in blank group (all P<0.01). The expression of HIT in resistance group was significantly higher than that in the control group, and the HIT expressions in interference group A and B were significantly lower than that in DDP-resistance and control group; moreover, the expression of HIT in over-expression group was significantly higher than that in blank group (all P<0.05 or P<0.01). The mRNAexpression of Snail in DDPresistance group was significantly higher than that in the control group and interference group A and B, while the mRNA expression of E-cadherin in DDP-resistance group was significantly lower than that in the control group and interference group A and B; and the mRNA expression of E-cadherin in over-expression group was significantly lower than that in blank group. The protein expression of Snail in the DDP-resistance group was significantly higher than that in the control group and interference group A and B,while E-cadherin protein expression was significantly lower; and protein expression of Snail in over-expression group was significantly higher than that in blank group (all P<0.05 or P<0.01). The expression of HIT in the U20S and 293T cells treated by anti-Snail antibody induced by immunomagnetic beads was significantly higher than that in the cells treated by IgG antibody (P<0.01). Conclusion: HIT can promote EMT and cisplatin-resistance in osteosarcoma cells through up-regulation of Snail protein and inhibition of E-cadherin transcription activity.

[Case-control study on close reduction and plaster slab fixation combined with plaster external traction for the treatment of pediatric Gartland type III supracondylar humerus fractures].

OBJECTIVE: To compare the therapeutic effects between close reduction and plaster slab fixation combined with plaster external traction and operation for the treatment of pediatric closed Gartland type III supracondylar humerus fractures without neurovascular injury complications. METHODS: From June 2009 to June 2012, 151 children with closed Gartland III supracondylar humerus fractures were retrospectively studied and divided into two groups, including 87 boys and 64 girls, ranging in age from 1 to 12 years old with an average of 5.3 years old. Among them, 76 children (conservative group) were treated with close reduction and plaster slab fixation combined with plaster external traction; 75 children (operation group) underwent surgical operation. The time of elbow joint function exercise, the healing time of fracture, the function recovery of elbow joint and carrying angle was recorded and analyzed. The therapeutic effects were evaluated by the Flynn criteria system. RESULTS: All patients were followed up from 6 to 36 months (18.3 months on average). The average time of fracture healing and elbow joint functional exercise of the conservative group was shorter than those of operation group (P < 0.001). Motion range of the elbows and carrying angle of two groups were no statistical difference (P > 0.05). According to Flynn criteria system, in conservative group, the result was excellent in 31 cases, good in 35, fair in 7, and poor in 3; in operation group, 27 in excellent, 30 in good, 17 in fair and 1 in poor; there was no significant difference between two groups in therapeutic effects (P > 0.05). CONCLUSION: Close reduction and plaster slab fixation combined with plaster external traction in treatment of pediatric closed Gartland type III supracondylar humerus fractures without neurovascular injury complications,which has similar effect to surgical treatment, and the time of fracture healing and elbow joint function exercise are significantly shorter.